DESCRIPTION: The search for an effective pharmacotherapy for the treatment of cocaine dependence has been elusive, but the serious medical and psychological morbidity and social costs of cocaine abuse underscore the need to continue research in the area of cocaine medications development. In this application, we propose studies to determine whether cocaine agonist (substitution) therapy with C2 substituted benzoyloxytropane analogs of cocaine might be safe and efficacious as pharmacotherapy treatments for cocaine dependence. The C2 substituted cocaine analogs, while sharing some pharmacological properties with cocaine, have other dissimilar properties that potentially make them useful as pharmacotherapeutic agents to treat cocaine dependence. We propose to use cocaethylene, the C2 ethyl ester of benzoylecgonine, as a prototype drug to test the concept that agonist treatment may block and/or produce tolerance to the acute effects of cocaine. This proposal will examine the question of the safety of cocaethylene administered to volunteers by examination of cocaethylene pharmacokinetics, physiological, and behavioral responses following infusion of the drug. A paradigm has also been developed based on preclinical studies showing induction of tolerance to acute cocaine responses in rodents which will be undertaken in human subjects. This protocol will determine whether tolerance to cardiovascular and subjective responses to cocaine can be induced following cocaethylene infusion. Positive findings from these studies could be followed in future studies with clinical trials to assess the efficacy of this class of drugs in the treatment of cocaine dependence.